scholarly journals Induction of dopaminergic neurons for neuronal subtype-specific modeling of psychiatric disease risk

2021 ◽  
Author(s):  
Samuel K. Powell ◽  
Callan O’Shea ◽  
Kayla Townsley ◽  
Iya Prytkova ◽  
Kristina Dobrindt ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Disease Risk ◽  
Psychiatric Disease ◽  
Neuronal Subtype ◽  
Specific Modeling

scholarly journals Induction of Dopaminergic Neurons for Neuronal Subtype-Specific Modeling of Psychiatric Disease Risk

2021 ◽  
Author(s):  
Samuel K Powell ◽  
Callan O'Shea ◽  
Kayla Townsley ◽  
Iya Prytkova ◽  
Kristina Dobrindt ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Dopaminergic Neuron ◽  
Disease Risk ◽  
Oscillatory Activity ◽  
Psychiatric Disease ◽  
Dopamine Synthesis ◽  
Neuron Development ◽  
Electrophysiological Properties ◽  
Midbrain Dopaminergic Neuron ◽  
Induced Pluripotent

Dopaminergic neurons are critical to movement, mood, addiction, and stress. Current techniques for generating dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) yield heterogenous cell populations with variable purity and inconsistent reproducibility between donors, hiPSC clones, and experiments. Here, we report the rapid (5 weeks) and efficient (~90%) induction of induced dopaminergic neurons (iDANs) through transient overexpression of lineage-promoting transcription factors combined with stringent selection across five donors. We observe maturation-dependent increase in dopamine synthesis, together with electrophysiological properties consistent with midbrain dopaminergic neuron identity, such as slow-rising after hyperpolarization potentials, an action potential duration of ~3ms, tonic sub-threshold oscillatory activity, and spontaneous burst firing at frequency of ~1.0-1.75 Hz. Transcriptome analysis reveals robust expression of genes involved in fetal midbrain dopaminergic neuron identity. Specifically expressed genes in iDANs, relative to their isogenic glutamatergic and GABAergic counterparts, were linked to the genetic risk architecture of a broad range of psychiatric traits, with iDANs showing particularly strong enrichment in loci conferring heritability for cannabis use disorder, schizophrenia, and bipolar disorder. Therefore, iDANs provide a critical tool for modeling midbrain dopaminergic neuron development and dysfunction in psychiatric disease.

scholarly journals The longitudinal stability of fMRI activation during reward processing in adolescents and young adults

2020 ◽  
Author(s):  
David AA Baranger ◽  
Morgan Lindenmuth ◽  
Melissa Nance ◽  
Amanda E. Guyer ◽  
Kate Keenan ◽  
...  
Keyword(s):  
Young Adults ◽  
Individual Difference ◽  
Disease Risk ◽  
Functional Neuroimaging ◽  
Reward Processing ◽  
Adolescents And Young Adults ◽  
Psychiatric Disease ◽  
Group Level ◽  
Neural Basis ◽  
Reward Function

AbstractBackgroundThe use of functional neuroimaging has been an extremely fruitful avenue for investigating the neural basis of human reward function. This approach has included identification of potential neurobiological mechanisms of psychiatric disease and examination of environmental, experiential, and biological factors that may contribute to disease risk via effects on the reward system. However, a central and largely unexamined assumption of much of this research is that neural reward function is an individual difference characteristic that is relatively stable over time.MethodsIn two independent samples of adolescents and young adults studied longitudinally (Ns = 145 & 153, 100% female & 100% male, ages 15-21 & 20-22, 2-4 scans & 2 scans respectively), we tested within-person stability of reward-task BOLD activation, with a median of 1 and 2 years between scans. We examined multiple commonly used contrasts of active states and baseline in both the anticipation and feedback phases of a card-guessing reward task. We examined the effects of cortical parcellation resolution, contrast, network (reward regions and resting-state networks), region-size, and activation strength and variability on the stability of reward-related activation.ResultsOverall, stability (ICC; intra-class correlation) across 1-2 years was modest. In both samples, contrasts of an active state relative to a baseline were more stable (e.g., Win>Baseline; mean ICC = 0.13 – 0.33) than contrasts of two active states (e.g., Win>Loss; mean ICC = 0.048 – 0.05). Additionally, activation in reward regions was less stable than in many non-task networks (e.g., dorsal attention), and activation in regions with greater between-subject variability showed higher stability in both samples.ConclusionsThese results show that functional neuroimaging activation to reward has modest stability over 1-2 years. Notably, results suggest that contrasts intended to map cognitive function and show robust group-level effects (i.e. Win > Loss) may be less effective in studies of individual differences and disease risk. The robustness of group-level activation should be weighed against other factors when selecting regions of interest in individual difference fMRI studies.

scholarly journals LRRK2 at Striatal Synapses: Cell-Type Specificity and Mechanistic Insights

Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 169
Author(s):  
Patrick D. Skelton ◽  
Valerie Tokars ◽  
Loukia Parisiadou
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Disease Risk ◽  
Lessons Learned ◽  
Striatal Neurons ◽  
Cell Type ◽  
Cell Type Specificity ◽  
A Cell ◽  
Cell Type Specific

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause Parkinson’s disease with a similar clinical presentation and progression to idiopathic Parkinson’s disease, and common variation is linked to disease risk. Recapitulation of the genotype in rodent models causes abnormal dopamine release and increases the susceptibility of dopaminergic neurons to insults, making LRRK2 a valuable model for understanding the pathobiology of Parkinson’s disease. It is also a promising druggable target with targeted therapies currently in development. LRRK2 mRNA and protein expression in the brain is highly variable across regions and cellular identities. A growing body of work has demonstrated that pathogenic LRRK2 mutations disrupt striatal synapses before the onset of overt neurodegeneration. Several substrates and interactors of LRRK2 have been identified to potentially mediate these pre-neurodegenerative changes in a cell-type-specific manner. This review discusses the effects of pathogenic LRRK2 mutations in striatal neurons, including cell-type-specific and pathway-specific alterations. It also highlights several LRRK2 effectors that could mediate the alterations to striatal function, including Rabs and protein kinase A. The lessons learned from improving our understanding of the pathogenic effects of LRRK2 mutations in striatal neurons will be applicable to both dissecting the cell-type specificity of LRRK2 function in the transcriptionally diverse subtypes of dopaminergic neurons and also increasing our understanding of basal ganglia development and biology. Finally, it will inform the development of therapeutics for Parkinson’s disease.

scholarly journals The psychiatric disease risk factors DISC1 and TNIK interact to regulate synapse composition and function

2010 ◽  
Vol 16 (10) ◽  
pp. 1006-1023 ◽  
Author(s):  
Q Wang ◽  
E I Charych ◽  
V L Pulito ◽  
J B Lee ◽  
N M Graziane ◽  
...  
Keyword(s):  
Risk Factors ◽  
Disease Risk ◽  
Psychiatric Disease ◽  
And Function

scholarly journals Distinct trans-placental effects of maternal immune activation by TLR3 and TLR7 agonists: implications for schizophrenia risk

2021 ◽  
Author(s):  
Jaedeok Kwon ◽  
Maria Suessmilch ◽  
Alison McColl ◽  
Jonathan Cavanagh ◽  
Brian J. Morris
Keyword(s):  
Disease Risk ◽  
Later Life ◽  
Maternal Blood ◽  
Maternal Plasma ◽  
Poly I:C ◽  
Psychiatric Disease ◽  
Mrna Levels ◽  
Pregnant Rats ◽  
Pregnant Mice ◽  
Virus Exposure

AbstractExposure to infection in utero predisposes towards psychiatric diseases such as autism, depression and schizophrenia in later life. The mechanisms involved are typically studied by administering mimetics of double-stranded (ds) RNA viral or bacterial infection to pregnant rats or mice. The effect of single-stranded (ss) virus mimetics has been largely ignored, despite evidence linking prenatal ss virus exposure specifically with psychiatric disease. Understanding the effects of gestational ss virus exposure has become even more important with the current SARS-CoV-2 pandemic. In this study, in pregnant mice, we compare directly the effects, on the maternal blood, placenta and the embryonic brain, of maternal administration of ds-virus mimetic poly I:C (to activate toll-like receptor 3, TLR3) and ss-virus mimetic resiquimod (to activate TLR7/8). We find that, 4h after the administration, both poly I:C and resiquimod elevated the levels of IL-6, TNFα, and chemokines including CCL2 and CCL5, in maternal plasma. Both agents also increased placental mRNA levels of IL-6 and IL-10, but only resiquimod increased placental TNFα mRNA. In foetal brain, poly I:C produced no detectable immune-response-related increases, whereas pronounced increases in cytokine (e.g. Il-6, Tnfα) and chemokine (e.g. Ccl2, Ccl5) expression were observed with maternal resiquimod administration. The data show substantial differences between the effect of maternal exposure to a TLR7/8 activator as compared to a TLR3 activator. There are significant implications for future modelling of diseases where maternal ss virus exposure contributes to environmental disease risk in offspring.

scholarly journals A longitudinal model of human neuronal differentiation for functional investigation of schizophrenia polygenic risk

2017 ◽  
Author(s):  
Anil P.S. Ori ◽  
Merel H.M. Bot ◽  
Remco T. Molenhuis ◽  
Loes M. Olde Loohuis ◽  
Roel A. Ophoff
Keyword(s):  
Neuronal Differentiation ◽  
Complex Traits ◽  
Disease Risk ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Experimental System ◽  
Analytical Framework ◽  
Psychiatric Disease ◽  
Cumulative Impact

AbstractThere is a pressing need for in vitro experimental systems that allow for interrogation of polygenic psychiatric disease risk to study the underlying biological mechanisms. We developed an analytical framework that integrates genome-wide disease risk from GWAS with longitudinal in vitro gene expression profiles of human neuronal differentiation. We demonstrate that the cumulative impact of risk loci of specific psychiatric disorders is significantly associated with genes that are differentially expressed across neuronal differentiation. We find significant evidence for schizophrenia, which is driven by a longitudinal synaptic gene cluster that is upregulated during differentiation. Our findings reveal that in vitro neuronal differentiation can be used to translate the polygenic architecture of schizophrenia to biologically relevant pathways that can be modeled in an experimental system. Overall, this work emphasizes the use of longitudinal in vitro transcriptomic signatures as a cellular readout and the application to the genetics of complex traits.

scholarly journals Factors Associated With Psychological Disturbances During the COVID-19 Pandemic: Multicountry Online Study

10.2196/28736 ◽  
2021 ◽  
Vol 8 (8) ◽  
pp. e28736
Author(s):  
Martyna Plomecka ◽  
Susanna Gobbi ◽  
Rachael Neckels ◽  
Piotr Radzinski ◽  
Beata Skorko ◽  
...  
Keyword(s):  
Mental Health ◽  
Disease Risk ◽  
Psychological Symptoms ◽  
Female Gender ◽  
Psychiatric Disease ◽  
Factors Associated ◽  
Online Study ◽  
Attitudes And Practices ◽  
Internet Users ◽  
Psychological Disturbances

Background Accumulating evidence suggests that the COVID-19 pandemic has negatively impacted the mental health of individuals. However, the susceptibility of individuals to be impacted by the pandemic is variable, suggesting potential influences of specific factors related to participants’ demographics, attitudes, and practices. Objective We aimed to identify the factors associated with psychological symptoms related to the effects of the first wave of the pandemic in a multicountry cohort of internet users. Methods This study anonymously screened 13,332 internet users worldwide for acute psychological symptoms related to the COVID-19 pandemic from March 29 to April 14, 2020, during the first wave of the pandemic amidst strict lockdown conditions. A total of 12,817 responses were considered valid. Moreover, 1077 participants from Europe were screened a second time from May 15 to May 30, 2020, to ascertain the presence of psychological effects after the ease down of restrictions. Results Female gender, pre-existing psychiatric conditions, and prior exposure to trauma were identified as notable factors associated with increased psychological symptoms during the first wave of COVID-19 (P<.001). The same factors, in addition to being related to someone who died due to COVID-19 and using social media more than usual, were associated with persistence of psychological disturbances in the limited second assessment of European participants after the restrictions had relatively eased (P<.001). Optimism, ability to share concerns with family and friends like usual, positive prediction about COVID-19, and daily exercise were related to fewer psychological symptoms in both assessments (P<.001). Conclusions This study highlights the significant impact of the COVID-19 pandemic at the worldwide level on the mental health of internet users and elucidates prominent associations with their demographics, history of psychiatric disease risk factors, household conditions, certain personality traits, and attitudes toward COVID-19.

scholarly journals Functional interrogation of a depression-related serotonergic SNP, rs6295, using a humanized mouse model

2018 ◽  
Author(s):  
Ashley M. Cunningham ◽  
Tabia L. Santos ◽  
Vanessa A. Gutzeit ◽  
Heather Hamilton ◽  
René Hen ◽  
...  
Keyword(s):  
Disease Risk ◽  
Psychiatric Disease ◽  
Null Mouse ◽  
Behavioral Alterations ◽  
Humanized Mouse Model ◽  
Protein Levels ◽  
Specific Effects ◽  
Cellular Context ◽  
And Behavior

AbstractThe serotonin 1A receptor (5-HT1A) system has been extensively implicated in modulating mood and behavior. Notably, 5-HT1A levels in humans display remarkable variation and differences in receptor levels have been linked with a variety of psychiatric disorders. Further, manipulation of receptor levels in mice suggests that changes in receptor levels that model existing human variation are sufficient to drive behavioral alterations. As a result, genetic mechanisms that modulate human 5-HT1A levels may be important for explaining individual differences in mood and behavior, representing a potential source of psychiatric disease risk. One common genetic variant implicated in differential 5-HT1A levels is the G/C single nucleotide polymorphism (SNP), rs6295, located upstream of the human 5-HT1A gene. This SNP differentially binds the transcription factor, NUDR/Deaf1, leading to cell-type specific effects on transcription in vitro. To investigate the direct effects of this SNP in the heterogeneous cellular context of the brain, we generated humanized transgenic mice using a design that maximized the local transcriptional landscape of the human HTR1A gene while also controlling for effects of genomic insertion location. Expression of the human transgene in a 5-HT1A null mouse resulted in line-dependent expression of human 5-HT1A. The effect of rs6295 on protein levels and behavior similarly differed across lines, suggesting that the penetrance of rs6295 may depend upon background genetic factors. Together, this work confirms that relatively subtle differences in 5-HT1A levels can contribute to differences in behavior and highlights the challenges of modeling human non-coding genetic variation in mice.

scholarly journals Mitochondrial roles of the psychiatric disease risk factor DISC1

2017 ◽  
Vol 187 ◽  
pp. 47-54 ◽  
Author(s):  
R. Norkett ◽  
S. Modi ◽  
J.T. Kittler
Keyword(s):  
Risk Factor ◽  
Disease Risk ◽  
Psychiatric Disease ◽  
Disease Risk Factor
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